Three Part Question

Clinical Scenario

A 36-week 3550 g neonate is admitted to the intensive care unit and commenced on intensive phototherapy for known Rhesus haemolytic disease. In spite of intensive phototherapy, the bilirubin level approaches the exchange transfusion threshold by hour 16 of life. The specialist registrar orders a crossmatch of blood and arranges for central line insertion in preparation for an exchange transfusion. The new registrar queries why intravenous immunoglobulin is not being used first in an attempt to avoid exchange transfusion.

Search Strategy

Search terms: [Neonatal hyperbilirubinaemia or hyperbilirubinaemia AND neonate or hyperbilirubinaemia and newborn] AND [ intravenous immunoglobulin or immunoglobulin]. Limit to newborn, human and English language.

Search Outcome

14 papers

Relevant Paper(s)

Author, date and country

Patient group

Study type (level of evidence)

Outcomes

Key results

Study Weaknesses

Alcock et al,2002

Total number of infants: 189

Cochrane systematic review of 3 RCTs

Exchange transfusion. Also mean number of exchange transfusions per infant

Comment(s)

Haemolytic disease of the newborn (HDN) is an isoimmune haemolytic jaundice which prior to modern interventions had a perinatal mortality rate of 50% that has now decreased to 7 per 100 000 births (Clarke). The mainstay of treatment is intensive phototherapy with exchange transfusion recommended if, in spite of phototherapy, the total serum bilirubin (TSB) approaches a level considered to cause a risk of bilirubin encephalopathy (Ip). However, Patra found that 74% of exchange transfusions were associated with an adverse event, most commonly thrombocytopenia (44%), hypocalcaemia (29%) and metabolic acidosis (24%).

Intravenous immunoglobulin (IVIG) has been used sporadically in the treatment of HDN to avoid exchange transfusion since the early 1990s (Sato). The exact mechanism of action is unknown but it is thought to inhibit haemolysis by blocking antibody receptors on red blood cells: IVIG occupies the Fc receptor sites thus competing with anti-D sensitised neonatal erythrocytes and preventing further haemolysis (Urbaniak). The 2004 American Academy of Pediatrics (AAP) guidelines recommend that in isoimmune haemolytic disease IVIG (0.5–1 g/kg over 2 h) should be administered if the total serum bilirubin (TSB) is rising despite intensive phototherapy or the TSB level is within 34–51 µmol/l (2–3 mg/dl) of the exchange level (Gottstein). If necessary, this dose can be repeated in 12 h.

The use of IVIG to avoid exchange transfusion in HDN has been explored in seven randomised controlled trials (RCT) and a Cochrane review for three of these studies (Alcock ). All RCTs showed a statistically significant reduction in the need for exchange transfusion with the use of IVIG, although Nasseri et al did find that when analysed separately, patients with ABO haemolytic disease showed no significant difference between IVIG and double surface blue light phototherapy. In Voto et al, however, the randomisation method is unclear, and in Rübo et al there was failure to report on an intention to treat basis. Only one study (Tanyer) looked at single versus multiple dose IVIG, and found that multiple dose IVIG resulted in a greater percentage reduction in the need for exchange transfusion.

IVIG is considered to be a reasonably safe product and is currently licensed and recommended for paediatric use in cases of fetal hydrops, primary immunodeficiencies, Kawasaki disease, alloimmune thrombocytopenia, autoimmune thrombocytopenic purpura and Gillian-Barre and in adult HIV related/associated thrombocytopenia. However, as a pooled blood product, the risk, albeit small, of transfusion transmitted disease remains despite viral partitioning and inactivation process (Yap). Serious side effects are very rare but include hypersensitivity and anaphylaxis. None of the studies of IVIG use for HDN reported any serious side effects. Only the study by Alpay et al reported any adverse effects, both of which were mild (one patient with hypocalcaemia and one with hypoglycaemia). None of these studies assessed long term outcome.

Two prospective studies again showed a reduction in the need for exchange transfusion (Mukhopadhyay, Hammerman). However, the criteria for administering IVIG in Hammerman et al resulted in it being administered at a lower SBR than in other studies. In Walsh et al (n = 11) there was a significant fall in SBR after IVIG administration and no exchange transfusions were required. Aggarwal et al (n = 26) used a cohort of patients all of whom received exchange transfusions within 6 h of birth and showed that IVIG administration reduced the need for subsequent exchange transfusions. The case series by Ergaz et al found a reduction in carboxyhaemoglobin levels (>30%) with the use of IVIG and exchange transfusion was avoided. This supports the theory that attenuation of jaundice by IVIG is, at least in part, attributable to a reduction in haemolysis. Additional studies also did not reveal any side effects of therapy with IVIG (Aylin, Sebag, Mundy, Merchant).

The NHS recently produced clinical guidelines for the use of immunoglobulin due to limited supply. The report suggests that IVIG may be used in selected cases of HDN with worsening hyperbilirubinaemia, terming this a grade B recommendation, level III evidence. The report references two studies (Ip, Alcock), one of which is a meta-analysis of RCTs (grade A, level 1a evidence). The other is the report of the AAP expert advisory group giving the number needed to treat with IVIG to prevent one exchange transfusion as 2.7. Therefore, the evidence presented by the NHS supports the selected use of IVIG in cases of HDN with worsening hyperbilirubinaemia.

Clinical Bottom Line

Intravenous immunoglobulin (IVIG) is a relatively safe and effective means of reducing the need for exchange transfusion in haemolytic disease of the newborn. (Grade A)

The American Academy of Pediatrics 2004 guidelines recommend administration of IVIG in isoimmune haemolytic disease if the total serum bilirubin (TSB) is rising despite intensive phototherapy or the TSB level is within 34–51 µmol/l (2–3 mg/dl) of the exchange level.